Mechanisms of onset of typical allergy are known to include the following steps. First, antigens foreign to the organism invade organisms. When exposed to these antigens, the organisms produce IgE antibodies against the antigens. Produced IgE adheres to the surface of mast cells to form IgE-bound mast cells. On renewed invasion of the antigens to the organisms with IgE-bound mast cells, antigen-antibody reactions occur at the surface of IgE-bound mast cells. As a result, various chemical mediators, such as histamine or leucotrienes, are released through degranulation of the IgE-bound mast cells. Allergic reactions occur by the actions of these chemical mediators.
To suppress these allergic reactions various drugs have been developed. For example, sodium cromoglycate is an antiallergic agent that suppresses the degranulation of mast cells and the release of chemical mediators such as histamine. It is used clinically as inhalant, nasal drops, ophthalmic preparations, and drugs for internal use as a superb preventive antiallergic agent. Especially, in the ophthalmologic field, it is used as ophthalmic preparations for allergic conjunctivitis and vernal conjunctivitis in Japan. However, since the mechanism of action of sodium cromoglycate lies in the inhibition of degranulation of mast cells, it cannot block the effects of chemical mediators already released. It is inferior in prompt action and must be administered about 4 weeks ahead of the onset of symptoms. Another drawback of sodium cromoglycate ophthalmic preparations is that it may produce eye-ache (irritating pain) at the time of instillation (Allergy Immunological and Clinical Aspects, A Wiley Medical Publication and JP-A-Sho 61-246117). Thus, sodium cromoglycate ophthalmic preparations are not satisfactory from the viewpoint of eye irritation.
Consequently, in order to add an effect of prompt onset to antiallergic ophthalmic preparations containing sodium cromoglycate, combination ophthalmic preparations have been developed in which sodium cromoglycate is formulated together with an antihistaminic that blocks released histamine. For example, a combination ophthalmic preparation containing 1.0% of sodium cromoglycate and 0.015% of chlorpheniramine maleate, an antihistaminic, has been subjected to clinical test in Japan (Igaku to Yakugaku 34(3) 507, 1995). Combination ophthalmic preparations containing sodium cromoglycate and chlorpheniramine maleate, an antihistaminic, are being used abroad (MARTINDALE The Extra Pharmacopoeia 30th Edition, The Pharmaceutical Press, 1993). These combination ophthalmic preparations containing sodium cromoglycate and an antihistaminic can produce a prompt antipruritic effect due to the antihistaminic, even when applied after the onset of allergic symptoms. However, the antipruritic effect of these ophthalmic preparations are not so strong as to prevent patients from scratching eyes due to severe itchiness, which results in development of inflammation of eye mucosa. Furthermore, since alleviation of the eye-irritating action was not taken into consideration, patients had to endure the pain upon use.
JP-A-Sho 61-246117 discloses that it is desirable to dissolve sodium cromoglycate in a solvent containing sodium bicarbonate and boric acid and adjust pH to neutral in order to alleviate the eye-ache at the time of instillation of the antiallergic ophthalmic preparation. However, sodium cromoglycate ophthalmic preparations having preventive antiallergic effects with prompt onset of action could not be obtained by the method described in the above publication. Furthermore, a supplementary test conducted by the present inventors by actually prescribing the formula revealed that the eye-irritating action of the sodium cromoglycate ophthalmic preparation was not satisfactorily alleviated.
Aromatics, represented by menthol, are frequently formulated into ophthalmic preparations as a refrigerant. For example, it is disclosed in a literature (Research Disclosure 31997) that the drug compliance by patients is improved by addition of aromatics to a sodium cromoglycate preparation. EP-A-670161 discloses a pharmaceutical composition comprising 0.1-10% of sodium cromoglycate, 0.005-0.2% of bicyclic aromatic (camphor, eucalyptus oil, or mixtures thereof), and an aqueous base.
However, an ophthalmic preparation containing 3 elements of sodium cromoglycate, an antihistaminic, and menthol has not been developed yet.